My take: This study shows that improvement in inflammation is associated with meaningful improvement in anemia. However, most patients will need additional treatment for anemia, particularly as anemia may be related to blood loss in addition to anemia of chronic disease/inflammation.

A useful review of microcytic anemia (NEJM 2014; 371: 1324-31) discusses the most common causes, mechanisms and treatment of microcytic anemia.

Common causes discussed include thalassemia, iron deficiency anemia, and anemia of inflammation. With the latter, the authors review the pathophysiology: “the cause of this anemia is twofold. First, renal production of erythropoietin is suppressed by inflammatory cytokines, resulting in decreased red-cell production. Second, lack of iron availability for developing red cells can lead to microcytosis. The lack of iron is largely due to the protein hepcidin, an acute-phase reactant that leads to both reduced iron absorption and reduced release of iron from body stores.”

Treatment of iron deficiency anemia –pointers:

Ferrous sulfate (325 mg [65 mg of elemental iron] orally three times a day -considered first line for adults. Ferrous gluconate at a daily dose of 325 mg [35 mg elemental] is an alternative.

“Several trials suggest that lower doses of iron, such as 15 to 20 mg of elemental iron daily can be as effective as higher doses and have fewer side effects.”

“There are many oral iron preparations, but no one compound appears to be superior to another.”

In those with an inadequate response to oral iron therapy, parenteral iron can be helpful. The authors note that low-molecular-weight iron dextran (INFeD) is “associated with an incidence of reactions that is similar to that with the newer products but allows for higher doses of iron replacement.” Typical dosing for adults: 25 mg test dose, and if tolerated for 1 hr, can give 975 mg (1000 mg total) over 4-6 hours. The low-molecular-weight iron dextran should not be used in patients with previous iron dextran hypersensitivity reactions.

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

The role of hepcidin in iron metabolism has been described in detail. Yet, a new study provides another line of evidence that the liver has a primary role in regulating iron absorption (Hepatology 2014; 59: 839-47, editorial 749-50).

Background: Hereditary hemochomatosis (HH) is mainly due to defects in the gene encoding the human hemochromatosis protein (HFE), particularly the C282Y mutation. Initially, HH was thought to be related to the role of HFE in regulation iron absorption at the intestinal crypt. However, the discovery of hepcidin, which is mainly secreted by the liver, was shown to regulate iron absorption through its interaction with ferroportin, the cellular iron exporter. With HH, inappropriately low hepcidin was associated with excessive iron absorption.

Despite this understanding, many questions remain, especially regarding the fact that some C282Y homozygotes have a normal serum ferritin and transferrin saturation. In addition, whether liver transplantation prevents further iron overload in patients transplanted for HH is not entirely certain.

Methods: This study evaluated 18 liver transplant (LT) patients with HH and who were homozygous for C282Y mutations. 16 of these patients had HCC. All patients underwent iron evaluations (iron, hepcidin, hepatic iron concentrations) prior to LT and most (n=11) had evaluations following LT with a median followup of 57 months.

Key findings:

After LT, no patients received iron depletion therapy (eg. phlebotomy). 9 of 11 had no iron overload based on bloodwork (normal transferrin saturation) and MRI without iron overload.

One patient with hereditary spherocytosis continued to have iron overload, and one patient with metabolic syndrome had mild iron overload.

Hepcidin was normal (11.12 nmol/L) in 10 patients at the end of followup and low in one patient with iron deficiency anemia; prior to LT, serum hepcidin levels were low in all patients (mean 0.54 nmol/L)

Bottomline: This study shows that LT corrects hepcidin dysregulation caused by the HFE mutation and that post-LT HH patients do not require phlebotomy. Thus, HH is clearly a liver disease and not an intestinal disease.

Amazingly, a group of investigators enrolled 25 healthy climbers to determine how hypoxia affects the expression of iron transporters in the duodenal mucosa (Hepatology 2013; 58: 2135-62).

Methods: In a nonblinded, prospective study, blood and duodenal samples were taken at three timepoints: baseline (446 meters) and at 4559 meters two days later after a rapid ascent and then at day four while remaining at high altitude. 14 subjects received dexamethasone on day 2 to avoid high-altitude sickness. The duodenal biopsies were obtained by unseated transnasal small-caliber duodenoscopy. Numerous other assays were checked as well.

Key finding: Hypoxemia was associated with a 10-fold increase in duodenal expression of divalent metal-ion transporter 1 and ferroportin 1 which promote iron intake. In addition, there was decreased serum hepcidin levels.

Take-home message: Hypoxic conditions such as high-altitude quickly lead to an activation of changes that lead to compensatory erythropoeisis.

As alluded to in a previous post (Help with hepcidin), hepcidin is integral to iron metabolism. In a recent study (J Pediatr 2012; 160: 949-53), serum and urine hepcidin concentrations in preterm infants were found to correlate well with iron homeostasis markers in preterm infants.

This study examined 31 preterm infants (23-32 weeks gestational age).

Findings:

Serum hepcidin was highest in infants with systemic inflammation.

Both serum and urine hepcidin correlated strongly with ferritin (Figure 2 in study) and negatively with soluble transferrin receptor/ferritin-ratio.

Serum ferritin levels were independently shown to be a risk factor for poor response to treatment in hepatitis C virus (HCV) infection (Hepatology 2012; 55: 1038-47). This article adds additional information to previous work which has shown that increased iron can be a comorbid factor in chronic viral hepatitis and other liver diseases.

This study used the Swiss Hepatitis C Cohort Study (SCCS) (n=3648). In this group, the success of treatment with pegylated interferon alpha and ribavirin were correlated with clinical and histological features.

Ferritin levels ≥ the sex-specific median values was one of the strongest pretreatment predictors of treatment failure (OR 0.45). It had a similar predictive effect as the IL28B genotype. In addition, higher ferritin levels were associated with severe liver fibrosis (OR 2.67) and steatosis (OR 2.29). For women the sex-specific median for ferritin level was 85 μg/L and for men it was 203 μg/L. The authors note that these cutoffs are quite close to the upper limits of normal of the general population (150 and 300 respectively).

Mechanistically, HCV interferes with the host’s iron metabolism leading to iron accumulation in the liver. Part of this is explained by down-regulation of hepcidin (Help with hepcidin). Part is due to ferritin acting as an acute phase reactant to inflammation. Ultimately, excess iron promotes liver inflammation, oxidative stress and mitochondrial dysfunction.

How important ferritin will be with newer therapies is not clear. It is likely that patients that are less responsive to dual therapy (pegylated interferon/ribavirin) will have poorer response as well to triple or quadruple therapies.

Over the past several years, the mechanisms involved in iron overload have been carefully examined and the genetic basis for most of these disorders is now understood. Several review articles on these disorders have been published; the most recent with excellent diagrams is in last week’s NEJM (NEJM 2012; 366: 348-59 & NEJM 2012; 366: 376-77). Although the process is quite complicated, the most important aspect regarding iron homeostasis is a feedback loop involving hepcidin-ferroportin. Hepcidin functions as a ‘hypoferremia hormone.’ It down regulates ferroportin release of iron into the circulation. Hepcidin is also an acute-phase protein and inflammation affects its function.

Hepcidin levels fluctuate in response to the body’s iron needs: more hepcidin causes less iron absorption & less hepcidin causes more iron absorption.

Iron balance disorders can usually be attributed to altered hepcidin production.

Anemia of chronic disease, though multifactorial, is mostly due to increased hepcidin production in response to inflammation.

Hemochromatosis results from genetic mutations causing lack of normal hepcidin production. The severity of these disorders correlates with hepcidin levels.

Hepcidin agonists could be used to treat hemochromatosis and other iron overload conditions (eg. thalassemia with transfusion therapy). For hemochromatosis, phlebotomy will be less expensive.

-NEJM 2005; 352: 1011. Algorithm. If transferrin saturation <16%, check ferritin. If ferritin less than 30, Fe-deficiency; if >100, anemia of chronic disease. If 30-100, check soluble transferrin receptor (level of sTranReceptor/log ferritin less than 1 is c/w anemia of chronic disease whereas when this ratio is greater than 2, c/w combined Fe-def anemia and anemia of chronic disease). Hepcidin is produced by hepatocytes and regulates iron homeostasis. Hepcidin interacts with ferroportin, an iron export protein on enterocytes (& other cells), & facilitates internalization and degradation of ferroportin. It may lead to decreased dietary iron absorption and to retention of iron body stores. Hepcidin expression can be up-regulated by high iron levels or during acute phase inflammatory responses (thus can contribute to anemia of chronic disease). Hereditary hemochromatosis associated with low hepcidin levels in the face of increased iron body stores. Several genes can affect hepcidin loss of function, including HFE, hemojuvelin (HJV), and transferrin receptor 2 (TFR2).